Tamper resistant pharmaceutical formulations

ABSTRACT

Disclosed in certain embodiments is a solid oral dosage form comprising a plurality of particles, each particle comprising (i) a core comprising an active agent susceptible to abuse and an internal adhesion promoter, wherein the cores are (i) dispersed in a matrix comprising a controlled release material or (ii) coated with a controlled release material. The dosage form can also include an alcohol resistant material.

FIELD OF THE INVENTION

The present invention relates to the field of pharmaceutical dosageforms that are resistant to tampering, abuse and/or alcohol dosedumping.

BACKGROUND

Pharmaceutical products are sometimes the subject of abuse. For example,a particular dose of opioid agonist may be more potent when administeredparenterally as compared to the same dose administered orally. Someformulations can be tampered with to provide the opioid agonistcontained therein for illicit use. Opioid agonist formulations intendedfor oral use are sometimes crushed or subject to extraction withsolvents (e.g., ethanol) by drug abusers to provide the opioid containedtherein for non-prescribed illicit use (e.g., nasal or parenteraladministration).

Controlled release oral dosage forms are sought out by abusers as thecrushing of the dosage form may liberate an amount of active agentotherwise intended for prolonged release (e.g., 12 to 24 hours), makingit immediately available. The immediate availability upon crushing mayalso make controlled release dosage forms more dangerous due to thepossibility of accidental overdose.

There have previously been attempts in the art to control the abusepotential associated with opioid analgesics. For example, thecombination of pentazocine and naloxone has been utilized in tabletsavailable in the United States, commercially available as Talwin® Nxfrom Sanofi-Winthrop. Talwin® Nx contains pentazocine hydrochlorideequivalent to 50 mg base and naloxone hydrochloride equivalent to 0.5 mgbase. Talwin® Nx is indicated for the relief of moderate to severe pain.The amount of naloxone present in this combination has low activity whentaken orally, and minimally interferes with the pharmacologic action ofpentazocine. However, this amount of naloxone given parenterally hasprofound antagonistic action to narcotic analgesics. Thus, the inclusionof naloxone is intended to curb a form of misuse of oral pentazocinewhich occurs when the dosage form is solubilized and injected.Therefore, this dosage has lower potential for parenteral misuse thanprevious oral pentazocine formulations. A fixed combination therapycomprising tilidine (50 mg) and naloxone (4 mg) has been available inGermany for the management of severe pain since 1978 (Valoron® N,Goedecke). The rationale for the combination of these drugs is effectivepain relief and the prevention of tilidine addiction throughnaloxone-induced antagonisms at the morphine receptor. A fixedcombination of buprenorphine and naloxone was introduced in 1991 in NewZealand (Temgesic® Nx, Reckitt & Colman) for the treatment of pain.

Commonly owned U.S. Patent Application Publication No. 20090081290 isdirected to opioid formulations that are resistant to crushing inattempts to liberate the drug contained therein for illicit use.

Commonly owned U.S. Patent Application Publication No. 20030068375 isdirected to opioid formulations that in certain embodiments include agelling agent in an effective amount to impart a viscosity unsuitablefor administration selected from the group consisting of parenteral andnasal administration to a solubilized mixture formed when the dosageform is crushed and mixed with from about 0.5 to about 10 ml of anaqueous liquid.

There exists a need in the art for a controlled release dosage formcontaining a drug susceptible to abuse that is resistant to providing animmediate release of the drug upon tampering. In the case of opioidanalgesics, there exists a need for a tamper resistant formulation thatdoes not solely rely upon the inclusion of an antagonist in theformulation to deter abuse.

All references described herein are hereby incorporated by reference intheir entireties for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of certain embodiments of the present invention toprovide a solid oral dosage form comprising a drug susceptible to abuse(e.g., an opioid analgesic), which is tamper-resistant.

It is an object of certain embodiments of the present invention toprovide a solid oral dosage form comprising a drug susceptible to abuse(e.g., an opioid analgesic), which is subject to less oral abuse thanother dosage forms.

It is an object of certain embodiments of the present invention toprovide a solid oral dosage form comprising a drug susceptible to abuse(e.g., an opioid analgesic), which is subject to less parenteral abusethan other dosage forms.

It is an object of certain embodiments of the present invention toprovide a solid oral dosage form comprising a drug susceptible to abuse(e.g., an opioid analgesic), which is subject to less intranasal abusethan other dosage forms.

It is a further object of certain embodiments of the present inventionto provide a solid oral dosage form comprising a drug susceptible toabuse (e.g., an opioid analgesic), which is subject to less diversionthan other dosage forms.

It is a further object of certain embodiments of the present inventionto provide a method of treating pain in human patients with a solid oraldosage form comprising an opioid analgesic while reducing the abusepotential of the dosage form.

It is a further object of certain embodiments of the present inventionto provide a solid oral dosage form comprising a drug susceptible toabuse (e.g., an opioid analgesic), which is resistant to dose dumping inthe presence of alcohol.

It is another object of certain embodiments of the present invention toprovide a method of manufacturing an oral dosage form of a drugsusceptible to abuse (e.g., an opioid analgesic) as disclosed herein.

It is another object of certain embodiments of the present invention toprovide a use of a medicament (e.g., an opioid analgesic) in themanufacture of a tamper-resistant dosage form as disclosed herein forthe treatment of a disease state (e.g., pain, diarrhea or constipation).

In other embodiments, the invention is directed to a method of preparingthe solid oral dosage forms disclosed herein, e.g., in tablet or capsuleform.

In further embodiments, the present invention is directed to a method oftreating a disease or condition (e.g., pain, diarrhea or constipation)comprising administering to a patient in need thereof an oral dosageform as disclosed herein.

One or more of the above objects, and others can be achieved by thepresent invention which in certain embodiments is directed to a solidoral dosage form comprising a plurality of particles, each particlecomprising a core comprising an active agent susceptible to abuse and aninternal adhesion promoter, wherein the cores are dispersed in a matrixcomprising a controlled release material. In other embodiments, thesolid oral dosage form comprises a plurality of particles, each particlecomprising (i) a core comprising an active agent susceptible to abuseand an internal adhesion promoter and (ii) a controlled release coatingcomprising a controlled release material layered on the core. In eachembodiment, the internal adhesion promoter promotes the adhesion of theactive agent and the controlled release material.

In certain embodiments, the present invention is directed to a solidoral dosage form comprising a plurality of particles, each particlecomprising a core comprising an active agent susceptible to abuse, adissolution enhancer and an internal adhesion promoter, wherein thecores are dispersed in a matrix comprising a controlled releasematerial. In other embodiments, the solid oral dosage form comprises aplurality of particles, each particle comprising (i) a core comprisingan active agent susceptible to abuse, a dissolution enhancer and aninternal adhesion promoter and (ii) a controlled release coatingcomprising a controlled release material layered on the core.

In certain embodiments, the present invention is directed to a solidoral dosage form comprising a plurality of particles, each particlecomprising a core comprising an active agent susceptible to abuse and aninternal adhesion promoter, wherein the cores are dispersed in a matrixcomprising a controlled release material and a pore former. In otherembodiments, the solid oral dosage form comprises a plurality ofparticles, each particle comprising (i) a core comprising an activeagent susceptible to abuse, an internal adhesion promoter and adissolution enhancer and (ii) a controlled release coating comprising acontrolled release material and a pore former, layered on the core.

In certain embodiments, the present invention is directed to a solidoral dosage form comprising a plurality of particles, each particlecomprising a core comprising an active agent susceptible to abuse, adissolution enhancer and an internal adhesion promoter, wherein thecores are dispersed in a matrix comprising a controlled release materialand an alcohol resistant material. In one embodiment, the cores canfirst be dispersed in the controlled release material (and optional poreformer) with the resultant dispersion further dispersed in the alcoholresistant material or vice versa. In another embodiment, the cores canbe dispersed simultaneously with both the controlled release materialand the alcohol resistant material. In other embodiments, the solid oraldosage form comprises a plurality of particles, each particle comprising(i) a core comprising an active agent susceptible to abuse, an internaladhesion promoter and a dissolution enhancer, (ii) a controlled releasecoating comprising a controlled release material and a pore former,layered on the core and (iii) an alcohol resistant coating comprising analcohol resistant material layered over the controlled release coating.

In certain embodiments, the present invention is directed to a solidoral dosage form comprising a plurality of particles, each particlecomprising a core comprising an active agent susceptible to abuse, adissolution enhancer and an internal adhesion promoter, wherein the coreis dispersed in a matrix comprising a controlled release material, analcohol resistant material and an external adhesion promoter. In oneembodiment, the cores can first be dispersed in the controlled releasematerial (and optional pore former) with the resultant dispersionfurther dispersed in the alcohol resistant material and externaladhesion promoter (or vice versa). In another embodiment, the cores canbe dispersed simultaneously with the controlled release material and thealcohol resistant material (and the optional external adhesionpromoter). In other embodiments, the solid oral dosage form comprises aplurality of particles, each particle comprising (i) a core comprisingan active agent susceptible to abuse, an internal adhesion promoter anda dissolution enhancer, (ii) a controlled release coating comprising acontrolled release material and a pore former, layered on the core and(iii) an alcohol resistant coating comprising an alcohol resistantmaterial and an external adhesion promoter layered over the controlledrelease coating.

In certain embodiments, the present invention is directed to a solidoral dosage form comprising a plurality of particles, each particlecomprising a core comprising an opioid agonist and a carbomer, whereinthe core is dispersed in a matrix comprising a neutral acrylic polymer,a pore former, an alkylcellulose and a carbomer. In one embodiment, thecores can first be dispersed in the neutral acrylic polymer (andoptional pore former) with the resultant dispersion further dispersed inthe alkylcellulose (and optional carbomer) (or vice versa). In anotherembodiment, the cores can be dispersed simultaneously with the neutralacrylic polymer and the alkylcellulose. In other embodiments, the solidoral dosage form comprises a plurality of particles, each particlecomprising (i) a core comprising an opioid agonist and a carbomer; (ii)a controlled release coating comprising a neutral acrylic polymer and apore former; and (iii) an alcohol resistant coating comprising analkylcellulose and a carbomer.

In certain embodiments, the present invention is directed to a processfor preparing a solid oral dosage form comprising preparing a pluralityof particles by (i) granulating an opioid agonist and a carbomer to formcore granules; (ii) mixing, granulating or coating the core granuleswith a neutral acrylic polymer and a pore former (e.g., lactose) toobtain controlled release particles (e.g., granules); (iii) mixing,granulating or coating the controlled release particles withmethylcellulose and a carbomer to obtain alcohol resistant controlledrelease particles (e.g., granules); and (iv) compressing the alcoholresistant controlled release particles into a tablet or filling theparticles in a capsule.

In certain embodiments, the solid oral dosage forms disclosed hereinprovide a controlled release of the active agent contained therein suchthat the dosage form is suitable for administration on a once daily(Q.D.) or twice daily (B.I.D.) basis.

In describing the present invention, the following terms are to be usedas indicated below. As used herein, the singular forms “a,” “an,” and“the” include plural references unless the context clearly indicatesotherwise. Thus, for example, reference to “a drug susceptible to abuse”includes a single active agent as well as a mixture of two or moredifferent active agents, and reference to a “gelling agent” includes asingle gelling agent as well as a mixture of two or more differentgelling agents, and the like.

As used herein, the terms “active agent,” “active ingredient,”“pharmaceutical agent,” and “drug” refer to any material that isintended to produce a therapeutic, prophylactic, or other intendedeffect, whether or not approved by a government agency for that purpose.These terms with respect to specific agents include all pharmaceuticallyactive agents, all pharmaceutically acceptable salts thereof, and allcomplexes, stereoisomers, crystalline forms, amorphous form,co-crystals, ether, esters, hydrates and solvates thereof, and mixturesthereof, which produce the intended effect.

As used herein, the terms “therapeutically effective” refers to theamount of drug or the rate of drug administration needed to produce adesired therapeutic result.

As used herein, the terms “prophylactically effective” refers to theamount of drug or the rate of drug administration needed to produce adesired prophylactic result.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith one or more chiral centers that are not mirror images of oneanother (diastereomers).

The term “enantiomer” or “enantiomeric” refers to a molecule that isnon-superimposable on its mirror image and hence optically activewherein the enantiomer rotates the plane of polarized light in onedirection by a certain degree, and its mirror image rotates the plane ofpolarized light by the same degree but in the opposite direction.

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “patient” means a subject who has presented a clinicalmanifestation of a particular symptom or symptoms suggesting the needfor treatment, who is treated preventatively or prophylactically for acondition, or who has been diagnosed with a condition to be treated.

“Pharmaceutically acceptable salts” include, but are not limited to,inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, tartrate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate and the like;amino acid salts such as arginate, asparaginate, glutamate and the like;metal salts such as sodium salt, potassium salt, cesium salt and thelike; alkaline earth metals such as calcium salt, magnesium salt and thelike; and organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like.

The term “subject” is inclusive of the definition of the term “patient”and does not exclude individuals who are entirely normal in all respectsor with respect to a particular condition.

The term “ppm” as used herein means “parts per million”. Regarding14-hydroxycodeinone, “ppm” means parts per million of14-hydroxycodeinone in a particular sample product. The14-hydroxycodeinone level can be determined by any method known in theart, preferably by HPLC analysis using UV detection.

The term “recovery” means the amount of drug obtained from the resultantsolution of a tampered dosage form (e.g., crushing and mixing in 5 or 10mL solvent) upon aspiration with a 27 gauge needle. In other embodimentsthe needle can be a different gauge, e.g., 18 gauge, 22 gauge or 25gauge.

The term “tampering” means a manipulation by mechanical, thermal, and/orchemical means to obtain a solution of drug available for illicit use.The tampering can be, e.g., by means of crushing and mixing then dosageform with a solvent (with or without heat), or by dissolution of anintact dosage form in a solvent (with or without heat).

The term “adhesion promoter” means a compound that maintains aninteraction (e.g., chemical or physical) between two other compounds tomaintain a desired characteristic of the interacted compounds. Forexample, an adhesion promoter of the present invention (e.g., carbomer,either internally or externally) maintains the interaction between theactive agent and the controlled release material such that a controlledrelease of the active agent is maintained, even when the dosage form iscrushed in an attempt to liberate the active agent for an immediaterelease. In another example, an adhesion promoter of the presentinvention (e.g., carbomer either internally or externally) maintains theinteraction between the controlled release material and the alcoholresistant material such that the dosage form does not dose dump in thepresence of alcohol.

The term “internal adhesion promoter” means a compound that is anadhesion promoter and is contained in the core of the dosage formsdisclosed herein.

The term “external adhesion promoter” means a compound that is anadhesion promoter and is contained outside the core of the dosage formsdisclosed herein

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A depicts a graphical representation of crush resistance of aformulation without an adhesion promoter.

FIG. 1B depicts a graphical representation of crush resistance of aformulation with HPMC as the adhesion promoter.

FIG. 1C depicts a graphical representation of crush resistance of aformulation with Nonoxynol 9 as the adhesion promoter.

FIG. 1D depicts a graphical representation of crush resistance of aformulation with Carbopol® 71G as the adhesion promoter.

FIG. 2 depicts a graphical representation of the dissolution of theformulations of Example 1B in SGF.

FIG. 3A depicts a graphical representation of the dissolution of theformulation of Example 1C with granules>600 μm in SGF.

FIG. 3B depicts a graphical representation of the dissolution of theformulation of Example 1C with granules<600 μm in SGF.

FIG. 4A depicts a graphical representation of the dissolution of theformulation of Example 1C with granules>600 μm with Carbopol® 71G inSGF.

FIG. 4B depicts a graphical representation of the dissolution of theformulation of Example 1C with granules<600 μm with Carbopol® 71G inSGF.

FIG. 5 is a graphical depiction of the dissolution of the formulation ofExample 1C with Carbopol® 71G in 40% EtOH/SGF.

FIG. 6 is a graphical depiction of the dissolution of the formulation ofExample 1D in 40% EtOH/SGF.

FIG. 7 is a graphical depiction of the dissolution of the formulation ofExample 1E without Carbopol® 71G in the external layer in 40% EtOH/SGF.

FIG. 8 is a graphical depiction of the dissolution of the formulation ofExample 1E with Carbopol® 71G in the external layer in 40% EtOH/SGF.

FIG. 9 is a graphical depiction of the dissolution of the formulation ofExample 1E with additional Carbopol® 71G in the external layer in 40%EtOH/SGF.

FIG. 10 is a graphical depiction of the dissolution of the formulationof Example 1E in SGF.

FIG. 11 is a graphical depiction of the dissolution of the formulationof Example 1E after milling in SGF.

FIG. 12A is a graphical depiction of the dissolution of the tabletformulation of Example 2 intact and crushed and milled in SGF.

FIG. 12B is a graphical depiction of the dissolution of the tabletformulation of Example 2 intact and crushed and milled in alcohol/SGF.

FIG. 13A is a graphical depiction of the extraction data from Example 3after 10 minutes.

FIG. 13B is a graphical depiction of the extraction data from Example 3after 60 minutes.

FIG. 14 is a graphical depiction of the syringability data from Example3.

FIG. 15A is a graphical depiction of the dissolution of the tablet andgranule formulation of Example 4A, milled and intact in SGF.

FIG. 15B is a graphical depiction of the dissolution of the tabletformulation of Example 4A, milled and intact in alcohol/SGF.

FIG. 16 is a graphical depiction of the dissolution of the tablet andgranule formulation of Example 4B, milled and intact SGF.

FIG. 17 is a graphical depiction of the dissolution of the granuleformulation of Example 4C, milled and intact in SGF.

FIG. 18A is a graphical depiction of the syringability data from Example5A.

FIG. 18B is a graphical depiction of the small volume extraction datafrom Example 5A.

FIG. 19A is a graphical depiction of the syringability data from Example5B.

FIG. 19B is a graphical depiction of the small volume extraction datafrom Example 5B.

FIG. 20A is a graphical depiction of the syringability data from Example5C.

FIG. 20B is a graphical depiction of the small volume extraction datafrom Example 5C.

FIG. 21 is a graphical depiction of the dissolution of the formulationof Example 6A in SGF.

FIG. 22 is a graphical depiction of the dissolution of the formulationof Example 6B, milled, crushed or intact in SGF.

FIG. 23 is a graphical depiction of the dissolution of the formulationof Example 6C, milled, crushed or intact in SGF.

FIG. 24A is a graphical depiction of the syringability data from Example6D.

FIG. 24B is a graphical depiction of the small volume extraction datafrom Example 6D.

FIG. 25 is a graphical depiction of the dissolution in SGF of theformulation of Example 7 intact and milled.

DETAILED DESCRIPTION

Controlled release dosage forms play a vital part in the management ofboth acute and chronic conditions (e.g., pain management with opioidanalgesics). Therefore, it is important to provide a tamper-resistantcontrolled release dosage form of a drug susceptible to abuse that maybe utilized to provide effective plasma levels to a patient according toan intended release profile, while not being susceptible to significantdose dumping when the dosage form is crushed, milled or tampered with byother means in an attempt to liberate the active agent contained thereinfor illicit use.

In certain embodiments, the dosage forms contained herein provide anin-vitro dissolution of the active agent contained therein indicative ofa controlled release profile such that it can be administered on a oncedaily or twice daily basis. By virtue of the present invention, when thedosage form is crushed according to the methods disclosed herein, thein-vitro dissolution profile is maintained, decreased or notsignificantly increased (e.g., by no more than a 30% increase at 1hour), such that the administration of a crushed dosage form would notlikely provide any more of a euphoric effect than the administration ofan intact dosage form.

In certain embodiments, the dosage forms contained herein provide anin-vitro dissolution of the active agent contained therein indicative ofa controlled release profile and when the dosage form is subject todissolution in an alcohol containing solvent (e.g., SGF with 40% EtOH)according to the methods disclosed herein, the in-vitro dissolutionprofile is maintained, decreased or not significantly increased (e.g.,by no more than a 20% increase at 1 hour), such that the administrationof dosage form with alcohol would not dose dump and would not likelyprovide any more of a euphoric effect than the administration of anintact dosage form. This attribute would also deter the tampering of thedosage form by dissolution in an alcohol containing solvent in anattempt to liberate the active agent contained therein for illicit use.

In certain embodiment, the present invention is directed to a solid oraldosage form comprising a plurality of particles, each particlecomprising a core comprising an active agent susceptible to abuse and aninternal adhesion promoter, wherein the cores are dispersed in a matrixcomprising a controlled release material. In other embodiments, thesolid oral dosage form comprises a plurality of particles, each particlecomprising (i) a core comprising an active agent susceptible to abuse(e.g., an opioid agonist) and (ii) a controlled release coatingcomprising a controlled release material layered on the core. The coremay further comprise an internal or external adhesion promoter topromote the adhesion of the active agent and the controlled releasematerial such that a controlled release profile is provided ormaintained when the dosage form is administered intact and/or thedissolution profile is maintained or not significantly changed when thedosage form is tampered with in an attempt to liberate the active agentcontained thereof or illicit use.

The core of the particles can also contain a dissolution enhancer tobalance the controlled release provided by the controlled releasematerial, such that enough active agent is released from the dosage formto provide a desired release profile and pharmacodynamic response.

In addition to, or in place of the dissolution enhancer in the dosageform, the controlled release coating of the particles may include a poreformer, that also may act to enhance the release of the active agentcontained therein such that enough active agent is released from thedosage form to provide a desired release profile and pharmacodynamicresponse.

In embodiments that are resistant to dissolution in alcohol containingsolvents, such resistance can be provided by an alcohol resistantmaterial mixed or granulated with, or coated over the controlled releasematerial. The alcohol resistant material may further comprise anexternal adhesion promoter to provide or enhance adhesion of the alcoholresistant material and the controlled release material in order toobtain, enhance or maintain the alcohol resistance characteristics ofthe dosage form.

In certain embodiments, the controlled release material is a polymerthat can modify the release rate of the active agent contained therein.Examples of polymers that can be utilized to modify the release of theactive agent include pharmaceutically acceptable cellulosic polymers,including but not limited to alkyl celluloses, cellulose esters,cellulose diesters, cellulose triesters, cellulose ethers, celluloseester-ethers, cellulose acylates, cellulose diacylates, cellulosetriacylates, cellulose acetates, cellulose diacetates, cellulosetriacetates, cellulose acetate propionates, cellulose acetate butyratesand mixtures thereof.

In other embodiments of the present invention, the controlled releasepolymer is a pharmaceutically acceptable acrylic polymer selectedwithout limitation from acrylic acid and methacrylic acid copolymers,methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamide copolymer,poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methylmethacrylate, polymethacrylate, poly(methyl methacrylate), poly(methylmethacrylate) copolymer, polyacrylamide, aminoalkyl methacrylatecopolymer, poly(methacrylic acid anhydride), glycidyl methacrylatecopolymers, and mixtures of any of the foregoing. Preferably, theacrylic polymer is a neutral acrylic polymer (e.g., Eudragit® NE 30 D,Eudragit® NE 40 D or Eudragit® NM 30 D), which can also providecrush-resistant characteristics to the individual particles. However,when the particles are crush resistant and compressed into a tablet, thetablet breaks apart wherein the tablet is subject to a typical forceused in tampering. In certain embodiments, the tablet has a breakingstrength of less than about 400N, less than about 350N, less than about300N or less than about 250N.

The internal adhesion promoter may be selected from the group consistingof a cellulosic material, a surfactant, a carbomer and a mixturethereof. In certain embodiments, the cellulosic material used as aninternal adhesion promoter is hydroxypropylmethylcellulose. In certainembodiments, the surfactant used as an internal adhesion promoter is anon-ionic surfactant such as a nonoxynol (e.g., nonoxynol-9) or asorbitan ester (e.g., Span® 20) and a mixture thereof.

In a particular embodiment, the internal adhesion promoter is an anionicpolymer such as a polyacrylic acid. The polyacrylic acid can be ahomopolymer and can be optionally crosslinked with a crosslinking agent(referred to as a carbomer). The cross-linking agent can be apolyalcohol allyl ether such as an allyl ether pentaerythritol, an allylether of sucrose, an allyl ether of propylene or a mixture thereof.

The dissolution enhancer, when utilized in the present invention, can bea pharmaceutically acceptable cellulosic polymer, including but notlimited to alkyl celluloses, cellulose esters, cellulose diesters,cellulose triesters, cellulose ethers, cellulose ester-ethers, celluloseacylates, cellulose diacylates, cellulose triacylates, celluloseacetates, cellulose diacetates, cellulose triacetates, cellulose acetatepropionates, cellulose acetate butyrates and mixtures thereof. In aparticular embodiment, the dissolution enhancer is methylcellulose. Thedissolution enhancer can also be a sugar (e.g., lactose or mannitol), astarch (e.g., sodium starch glycolate) or a polymer (e.g.,crospovidone).

The pore former, when utilized in the present invention, can be a watersoluble material that enhances release by creating channels orpassageways in the controlled release coating, or by otherwise weakeningthe integrity of the coating upon exposure to an environmental fluid.The pore former can be a polysaccharide such as lactose, sucrose,dextrose, mannitol, d-mannitol, alpha-d-lactose monohydrate, glucose ormixture thereof, a cellulosic material such as microcrystallinecellulose, hydroxypropylmethylcellulose or a mixture thereof, or amaterial such as polyvinyl alcohol. The pore former can also be a watersoluble polymer such as polyethylene glycol, povidone, poloxamer andcombinations thereof. The pore former can also be an organic solventsuch as propylene glycol. Other materials that can be pore formersinclude osmagents or osmotic agents such as organic and inorganiccompounds. Such agents can include salts, acids, bases, chelatingagents, sodium chloride, calcium sulfate, calcium phosphate, lithiumchloride, magnesium chloride, magnesium sulfate, lithium sulfate,potassium chloride, sodium sulfite, calcium bicarbonate, sodium sulfate,calcium lactate, urea, tartaric acid, raffinose, and combinationsthereof.

More specifically, the pore former can be a salt which is water-solubleand pharmaceutically acceptable. The cations of these salts can bealkali metals such as sodium and potassium, alkaline earth metals suchas magnesium, calcium and barium, or other cations such as ammonium,ferric, etc. The anions may include 1-hydroxy-2-naphthoic acid,2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaricacid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid,adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid,benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capricacid (decanoic acid), caproic acid (hexanoic acid), caprylic acid(octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, formic acid, fumaric acid, galactaric acid, gentisic acid,glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamicacid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid(DL), lactobionic acid, lauric acid, maleic acid, malic acid (−L),malonic acid, mandelic acid (DL), methanesulfonic acid,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinicacid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid,phosphoric acid, proprionic acid, pyroglutamic acid (−L), salicylicacid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaricacid (+L), thiocyanic acid, toluenesulfonic acid (p) and undecylenicacid.

The alcohol resistant material utilized in the present invention can beany pharmaceutically acceptable material that is capable of providingresistance to dissolution in an alcohol containing solvent. The alcoholresistant material may be an alkylcellulose such as methylcellulose.

The external adhesion promoter may be selected from the group consistingof a cellulosic material, a surfactant, a carbomer and a mixturethereof. The external adhesion promoter can be the same or differentthan the internal adhesion promoter. In certain embodiments, thecellulosic material used as an external adhesion promoter ishydroxypropylmethylcellulose. In certain embodiments, the surfactantused as an external adhesion promoter is a non-ionic surfactant such asa nonoxynol (e.g., nonoxynol-9) or a sorbitan ester (e.g., Span® 20) anda mixture thereof.

In a particular embodiment, the external adhesion promoter is an anionicpolymer such as a polyacrylic acid. The polyacrylic acid can be ahomopolymer and can be optionally crosslinked with a crosslinking agent(a carbomer). The cross-linking agent can be a polyalcohol allyl ethersuch as an allyl ether pentaerythritol, an allyl ether of sucrose, anallyl ether of propylene or a mixture thereof.

A unit dose of a plurality of particles of the present invention can beadministered in any suitable form, e.g., in a capsule (e.g., a gelatincapsule), contained in a powder paper, or compressed into a tablet.

The dosage forms of the present invention can be prepared by mixing theactive agent and the adhesion promoter together to form a plurality ofcores. The cores can be prepared by granulating the materials to formcore granules, by compression of a mixture of the components, or bylayering the components over an inert substance such as non-pareilbeads.

The core granules can then be mixed, granulated or coated with thecontrolled release material and the optional pore former to obtaincontrolled release particles. This process may include spray coating thecore particles (e.g., core granules) with the controlled releasematerial and optional pore former or by granulating the core particleswith the controlled release material and optional pore former.

The controlled release particles can then be mixed, granulated or coatedwith alcohol resistant material to obtain alcohol resistant controlledrelease particles. This process may include spray coating the controlledrelease particles (e.g., controlled release granules) with the alcoholresistant material and optional external adhesion promoter or bygranulating the controlled release particles with the alcohol resistantmaterial and optional external adhesion promoter.

The alcohol resistant controlled release particles can then be containedwithin a pharmaceutically acceptable capsule or compressed into atablet.

In certain embodiments, the weight ratio of the active agent to thecontrolled release material is from about 2:1 to about 1:100; from about1:5 to about 1:50; from about 1:1 to about 1:75 or from about 1:10 toabout 1:30.

In certain embodiments, the particles can have a mean diameter fromabout 0.1 mm to about 2 mm; from about 0.2 mm to about 1 mm; or fromabout 0.3 mm to about 0.8 mm.

In certain embodiments, the solid oral dosage form of the presentinvention comprises from about 0.1% to about 80% (w/w) active agent;from about 0.5% to about 60% (w/w) active agent; from about 1% to about40% (w/w) active agent; from about 0.1% to about 30% (w/w) active agent;from about 0.5% to about 20% (w/w) active agent; from about 1% to about10% (w/w) active agent or from about 1% to about 5% active agent.

In certain embodiments, the solid oral dosage form of the presentinvention comprises from about 10% to about 90% (w/w) controlled releasematerial; from about 25% to about 75% (w/w) controlled release material;or from about 40% to about 60% (w/w) controlled release material.

In certain embodiments, the solid oral dosage form of the presentinvention comprises from about 0.05% to about 10% (w/w) internaladhesion promoter; from about 0.1% to about 5% (w/w) internal adhesionpromoter; or from about 0.5% to about 3% (w/w) internal adhesionpromoter.

In certain embodiments, the solid oral dosage form of the presentinvention comprises from about 1% to about 40% (w/w) dissolutionenhancer; from about 5% to about 30% (w/w) dissolution enhancer; or fromabout 10% to about 20% (w/w) dissolution enhancer.

In certain embodiments, the solid oral dosage form of the presentinvention comprises from about 0.5% to about 25% (w/w) pore former; fromabout 1% to about 15% (w/w) pore former; or from about 2% to about 10%(w/w) pore former.

In certain embodiments, the solid oral dosage form of the presentinvention comprises from about 1% to about 50% (w/w) alcohol resistantmaterial; from about 5% to about 40% (w/w) alcohol resistant material;or from about 10% to about 30% (w/w) alcohol resistant material.

In certain embodiments, the solid oral dosage form of the presentinvention comprises from about 0.5% to about 15% (w/w) external adhesionpromoter; from about 1% to about 10% (w/w) external adhesion promoter;or from about 2% to about 8% (w/w) external adhesion promoter.

In certain embodiments, the solid oral dosage form of the presentinvention provides a dissolution release rate in-vitro of the activeagent, when measured by the USP Type 2, Paddle Method at 50 rpm in 900ml Simulated Gastric Fluid (SGF) without enzymes at 37° C. of at leastabout 15% by weight of the active agent released at 1 hour, from about25% to about 65% by weight of the active agent released at 2 hours, fromabout 45% to about 85% by weight of the active agent released at 4hours, and at least about 60% by weight of the active agent released at8 hours.

In certain embodiments, the solid oral dosage form of the presentinvention provides a dissolution release rate in-vitro of the activeagent, when measured by the USP Type 2, Paddle Method at 50 rpm in 900ml Simulated Gastric Fluid (SGF) without enzymes at 37° C. of at leastabout 20% by weight of the active agent released at 4 hours, from about20% to about 65% by weight of the active agent released at 8 hours, fromabout 45% to about 85% by weight of the active agent released at 12hours, and at least about 80% by weight of the active agent released at24 hours.

In certain embodiments, the amount of active agent released from thedosage forms of the present invention at 0.5 hour, 1 hour, 2 hoursand/or 4 hours when measured in a USP Type 2, Paddle Method at 50 rpm in900 ml simulated gastric fluid (SGF) without enzymes with 40% ethanol at37° C., is within 30% (higher or lower) of the amount of active agentreleased at the same time period when measured in a USP Type 2, PaddleMethod at 50 rpmin 900 ml simulated gastric fluid without enzymes (SGF)with 0% ethanol at 37° C.

In certain embodiments, the amount of active agent released from thedosage forms of the present invention at 0.5 hour, 1 hour, 2 hoursand/or 4 hours when measured in a USP Type 2, Paddle Method at 50 rpm in900 ml simulated gastric fluid (SGF) without enzymes with 40% ethanol at37° C., is within 25% (higher or lower) of the amount of active agentreleased at the same time period when measured in a USP Type 2, PaddleMethod at 50 rpm in 900 ml simulated gastric fluid without enzymes (SGF)with 0% ethanol at 37° C.

In certain embodiments, the amount of active agent released from thedosage forms of the present invention at 0.5 hour, 1 hour, 2 hoursand/or 4 hours when measured in a USP Type 2, Paddle Method at 50 rpm in900 ml simulated gastric fluid (SGF) without enzymes with 40% ethanol at37° C., is within 20% (higher or lower) of the amount of active agentreleased at the same time period when measured in a USP Type 2, PaddleMethod at 50 rpm in 900 ml simulated gastric fluid without enzymes (SGF)with 0% ethanol at 37° C.

In certain embodiments, the amount of active agent released from thedosage forms of the present invention at 0.5 hour, 1 hour, 2 hoursand/or 4 hours when measured in a USP Type 2, Paddle Method at 50 rpm in900 ml simulated gastric fluid (SGF) without enzymes with 40% ethanol at37° C., is within 10% (higher or lower) of the amount of active agentreleased at the same time period when measured in a USP Type 2, PaddleMethod at 50 rpm in 900 ml simulated gastric fluid without enzymes (SGF)with 0% ethanol at 37° C.

In certain embodiments, the amount of active agent released from thedosage forms of the present invention at 0.5 hour, 1 hour, 2 hoursand/or 4 hours when measured in a USP Type 2, Paddle Method at 50 rpm in900 ml simulated gastric fluid (SGF) without enzymes with 40% ethanol at37° C., is within 5% (higher or lower) of the amount of active agentreleased at the same time period when measured in a USP Type 2, PaddleMethod at 50 rpm in 900 ml simulated gastric fluid without enzymes (SGF)with 0% ethanol at 37° C.

In certain embodiments, the amount of active agent released at 0.5 hour,1 hour, 2 hours or 4 hours when measured in a USP Type 2, Paddle Methodat 50 rpm in 900 ml simulated gastric fluid (SGF) without enzymes with40% ethanol at 37° C., is less than the amount of active agent releasedat the same time period when measured in a USP Type 2, Paddle Method at50 rpm in 900 ml simulated gastric fluid without enzymes (SGF) with 0%ethanol at 37° C.

In certain embodiments, the amount of active agent released from acrushed dosage form at 0.5 hour, 1 hour, 2 hours or 4 hours whenmeasured in a USP Type 2, Paddle Method at 50 rpm in 900 ml simulatedgastric fluid (SGF) without enzymes at 37° C., is within 30% (higher orlower) of the amount of active agent released from an intact dosage format the same time period when measured in a USP Type 2, Paddle Method at50 rpm in 900 ml simulated gastric fluid without enzymes (SGF) with 0%ethanol at 37° C.

In certain embodiments, the amount of active agent released from acrushed dosage form at 0.5 hour, 1 hour, 2 hours or 4 hours whenmeasured in a USP Type 2, Paddle Method at 50 rpm in 900 ml simulatedgastric fluid (SGF) without enzymes at 37° C., is within 25% (higher orlower) of the amount of active agent released from an intact dosage format the same time period when measured in a USP Type 2, Paddle Method at50 rpm at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) with 0% ethanol at 37° C.

In certain embodiments, the amount of active agent released from acrushed dosage form at 0.5 hour, 1 hour, 2 hours or 4 hours whenmeasured in a USP Type 2, Paddle Method at 50 rpm in 900 ml simulatedgastric fluid (SGF) without enzymes at 37° C., is within 20% (higher orlower) of the amount of active agent released from an intact dosage format the same time period when measured in a USP Type 2, Paddle Method at50 rpm in 900 ml simulated gastric fluid without enzymes (SGF) with 0%ethanol at 37° C.

In certain embodiments, the amount of active agent released from acrushed dosage form at 0.5 hour, 1 hour, 2 hours or 4 hours whenmeasured in a USP Type 2, Paddle Method at 50 rpm in 900 ml simulatedgastric fluid (SGF) without enzymes at 37° C., is within 15% (higher orlower) of the amount of active agent released from an intact dosage format the same time period when measured in a USP Type 2, Paddle Method at50 rpm in 900 ml simulated gastric fluid without enzymes (SGF) with 0%ethanol at 37° C.

In certain embodiments, the amount of active agent released from acrushed dosage form at 0.5 hour, 1 hour, 2 hours or 4 hours whenmeasured in a USP Type 2, Paddle Method at 50 rpm in 900 ml simulatedgastric fluid (SGF) without enzymes at 37° C., is within 10% (higher orlower) of the amount of active agent released from an intact dosage format the same time period when measured in a USP Type 2, Paddle Method at50 rpmin 900 ml simulated gastric fluid without enzymes (SGF) with 0%ethanol at 37° C.

In certain embodiments, the amount of active agent released from acrushed dosage form at 0.5 hour, 1 hour, 2 hours or 4 hours whenmeasured in a USP Type 2, Paddle Method at 50 rpm in 900 ml simulatedgastric fluid (SGF) without enzymes at 37° C., is within 5% (higher orlower) of the amount of active agent released from an intact dosage format the same time period when measured in a USP Type 2, Paddle Method at50 rpm in 900 ml simulated gastric fluid without enzymes (SGF) with 0%ethanol at 37° C.

The dosage forms of the present invention can include additionalexcipients in order to, e.g., aid manufacturing, provide additionaltamper resistance, further modify the release rate, or further modifyalcohol resistance.

Additional excipients may include at least one excipient selected fromthe group consisting of bulking agents or fillers, plasticizers,stabilizers, diluents, lubricants, disintegrants, binders, granulatingaids, colorants, flavorants, anti-oxidants, and glidants.

Suitable anti-oxidants include organic acids, carboxylic acids, acidsalts of amino acids, sodium metabisulphite, ascorbic acid and itsderivatives, malic acid, isoascorbic acid, citric acid, tartaric acid,sodium sulphite, sodium bisulphate, tocopherol, water- and fat-solublederivatives of tocopherol, sulphites, bisulphites and hydrogensulphites, butylated hydroxyanisol (BHA) or butylated hydroxytoluene(BHT), 2,6-di-t-butyl-alpha-dimethylamino-p-cresol, t-butylhydroquinone,di-t-amylhydroquinone, di-t-butylhydroquinone, butylhydroxytoluene,butylhydroxyanisole, pyrocatechol, pyrogallol, propyl gallate, andnordihydroguaiaretic acid, phosphoric acids, sorbic and benzoic acids,esters, derivatives and isomeric compounds, vitamin E, ascorbylpalmitate, ethylenediaminetetraacetic acid, cysteine, pharmaceuticallyacceptable salts thereof, and mixtures thereof. Specific combinations ofanti-oxidants include BHT and BHA; BHA and propyl gallate; BHT, BHA andsodium metabisulphite; BHA and citric acid; vitamin E and ascorbylpalmitate; and BHA, BHT and ethylenediaminetetraacetic acid.

The drug susceptible to abuse can be dry-blended with the internaladhesion promoter and any additional excipients prior to being formedinto core particles. In certain embodiments, the materials can bewet-granulated, dried, and optionally milled to prepare the coreparticles.

In certain embodiments, the controlled release material can be includedin the core particles, alternatively, or in addition to, the controlledrelease matrix or coating. The controlled release matrix or coating caninclude one or more controlled release materials and optional poreformer and be mixed with, granulated with or layered over the coreparticles to achieve a weight gain, e.g., of from about 1% to about500%, from about 25% to about 400%, or from about 50% to about 300%(w/w).

The dosage forms can also include a coating to enhance cosmeticappearance and/or to reduce tackiness. Examples of materials to beutilized as a film coat include hydroxypropylmethylcellulose, polyvinylalcohol, lactose, and mixtures thereof. The film coat can be: (i) anouter coating directly coated onto a dosage form (e.g., a compressedtablet or an individual particle), or (ii) an intermediate coatingbetween the core and the controlled release matrix or coating and/or thecontrolled release matrix or coating and the alcohol resistant matrix orcoating.

In certain embodiments, the plurality of particles can be combined withadditional excipients prior to being compressed into a tablet. Suchadditional excipients can be disintegrants, fillers, flow aids,lubricants and gelling agents. The gelling agent can be in an amount tobe an aversive agent by forming a viscous solution upon introductionwith a small amount of a solvent. The resultant viscosity would hinderthe ability to have the active agent contained therein administered bythe parenteral or nasal route.

The disintegrant can be an agent such as, e.g., polyvinylpyrrolidone,sodium starch glycolate, crosscarmellose sodium, or a mixture thereof.The filler or diluent can be an agent such as, e.g., lactose, dextrose,mannitol, microcrystalline cellulose, or a mixture thereof.

The gelling agent utilized in certain embodiments of the presentinvention can be selected from sugars, sugar derived alcohols (e.g.,mannitol, sorbitol, and the like), starch and starch derivatives,cellulose derivatives (e.g., microcrystalline cellulose, sodiumcarboxymethyl cellulose, methylcellulose, ethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose),attapulgites, bentonites, dextrins, alginates, carrageenan, gums (e.g.,gum tragacanth, gum acacia, guar gum, and xanthan gum), pectin, gelatin,kaolin, lecithin, magnesium aluminum silicate, polyvinylpyrrolidone,polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicondioxide, curdlan, furcelleran, egg white powder, lacto albumin, soyprotein, chitosan, surfactants, mixed surfactant/wetting agent systems,emulsifiers, other polymeric materials, and mixtures thereof. In certainembodiments, the gelling agent is xanthan gum. In other embodiments, thegelling agent is pectin. The pectin or pectic substances includepurified or isolated pectates and crude natural pectin from sources suchas apple, citrus or sugar beet residues which have been subjected, whennecessary, to esterification or de-esterification (e.g., by alkali orenzymes). The pectins may also be derived from citrus fruits such aslime, lemon, grapefruit, and orange. In particular embodiments, thegelling agent may be selected from the group consisting ofpregelatinized starch (e.g., Swelstar® from Asahi Kasei),hydroxyethylcellulose (e.g., Natrosol® from Ashland Inc.), guar gum(e.g., Supercol® from Ashland Inc.), xanthan gum, alginate, carrageenan,polyethylene oxide and a mixture thereof.

In addition to gelling agents, the dosage forms of the present inventioncan include other aversive agents to further deter the illicit use ofthe drug contained therein. These other aversive agents can be, e.g., anemetic, an antagonist, a bittering agent, an irritant, or a mixturethereof. They can be incorporated into the particles, or addedseparately within a capsule or as additional tableting excipients.

The emetic may be selected from, e.g., the group consisting of methylcephaeline, cephaeline, emetine hydrochloride, psychotrine,O-methylpsychotrine, emetamine, ipecamine, hydro-ipecamine, ipecacunhicacid and mixtures thereof. In particular embodiments, the emetic isipecac.

The antagonist may be selected from, e.g., the group consisting ofnaltrexone, naloxone, nalmefene, cyclazacine, levallorphan,pharmaceutically acceptable salts thereof, and mixtures thereof.

The bittering agent may be selected from, e.g., the group consisting offlavor oils, flavoring aromatics, oleoresins, plant extracts, leafextracts, flower extracts, fruit extracts, sucrose derivatives,chlorosucrose derivatives, quinine sulphate, denatonium benzoate andmixtures thereof. In certain embodiments, the bittering agent isspearmint oil, peppermint oil, eucalyptus oil, oil of nutmeg, allspice,mace, oil of bitter almonds, menthol or a mixture thereof. In otherembodiments, the bittering agent extracted from a fruit is selected fromthe group consisting of lemon, orange, lime, grapefruit, and mixturesthereof. In a particular embodiment, the bittering agent is denatoniumbenzoate.

The irritant may be selected from, e.g., a surfactant, capsaicin or acapsaicin analog. The capsaicin analog can be selected from the groupconsisting of resiniferatoxin, tinyatoxin, heptanoylisobutylamide,heptanoyl guaiacylamide, an isobutylamide, a guaiacylamide,dihydrocapsaicin, homovanillyl octylester, nonanoyl vanillylamide, andmixtures thereof.

The surfactant can be selected from the group consisting of poloxamer, asorbitan monoester, a glyceryl monooleate, sodium lauryl sulfate andmixtures thereof.

The surfactant can be included in the dosage form in an amount, e.g.,from about 1% to about 25% (w/w) of the dosage form; from about 4% toabout 15% (w/w) of the dosage form; from about 2.5% to about 10% (w/w)of the dosage form or from about 8% to about 12% (w/w) of the dosageform.

In embodiments using gelling agents, the solid oral dosage forms of thepresent invention when mixed or crushed and mixed (with or without heat)with from about 0.5 to about 10 ml of distilled water, provides aviscosity that prevents or reduces the ability of the drug from beingdrawn up into a syringe, or systemically absorbed when parenteral ornasal administration is attempted.

In certain embodiments, the viscosity after tampering with from about0.5 to about 10 ml of distilled water is at least about 10 cP, at leastabout 50 cP, at least about 100 cP, at least about 500 cP or at leastabout 1,000 cP.

In certain embodiments, the viscosity after tampering with from about0.5 to about 10 ml of distilled water is from about 50 cP to about100,000 cP; from about 75 cP to about 50,000 cP; from about 100 cP toabout 25,000 cP; from about 150 cP to about 10,000 cP; from about 200 cPto about 5,000 cP; or from about 250 cP to about 1,000 cP.

In certain embodiments, the recovery of the drug is, e.g., less thanabout 50%, less than about 40%, less than about 30%, less than about20%, less than about 10%, less than about 8%, less than about 6%, lessthan about 4%, less than about 2%, less than about 1%, less than about0.8%, less than about 0.6%, less than about 0.4%, or less than less thanabout 0.2%, based on a syringability test whereby the dosage form ismixed or crushed and mixed with 5 or 10 mL solvent and the resultantsolution is aspirated with a 18, 22, 25 or 27 gauge needle.

The solvent utilized in the syringability test can be, e.g., tap water,distilled water, sterile saline, vinegar or 40% ethanol. Also, duringthe syringability test, the solvent (before or after mixing with thedosage form) can be subject to heat from any source such as, e.g., bythe use of a butane lighter.

In certain embodiments of the present invention, the recovery of thedrug is, e.g., less than about 10%, less than about 8%, less than about6%, less than about 4%, less than about 2%, less than about 1%, lessthan about 0.8%, less than about 0.6%, less than about 0.4%, or lessthan less than about 0.2%, based on both heated and unheatedsyringability tests, whereby the dosage form is mixed or crushed andmixed with 5 or 10 mL solvent and the resultant solution is aspiratedwith a 18, 22, 25 or 27 gauge needle.

In certain embodiments, the ratio of extraction from an unheatedsyringability test to a heated syringability test is from about 1:5 toabout 5:1; from about 1:4 to about 4:1; from about 1:3 to about 3:1;from about 1:2 to about 2:1; from about 1:1.5 to about 1.5:1; from about1:1.3 to about 1.3:1 or from about 1:1.1 to about 1.1:1.

In certain embodiments of the present invention, the recovery of thedrug from small volume extraction at 10 minutes and/or 60 minutes is,e.g., less than about 90%, less than about 80%, less than about 70%,less than about 60%, less than about 50%, less than about 40%, less thanabout 30%, less than about 20%, less than about 10%, less than about 8%,less than about 6%, less than about 4%, less than about 2%, less thanabout 1%, less than about 0.8%, less than about 0.6%, less than about0.4%, or less than less than about 0.2%, based on both heated andunheated extraction tests, whereby the dosage form is mixed or crushedand mixed with 30 mL of a solvent. The small volume extraction can bemeasured, e.g., by the procedures of Example 3.

In certain embodiments, the ratio of extraction from an unheated smallvolume extraction test at 10 minutes and/or 60 minutes to acorresponding heated extraction test is from about 1:50 to about 50:1;from about 1:40 to about 40:1; from about 1:30 to about 30:1; from about1:20 to about 20:1; from about 1:10 to about 10:1; from about 1:5 toabout 5:1; from about 1:4 to about 4:1; from about 1:3 to about 3:1;from about 1:2 to about 2:1; from about 1:1.5 to about 1.5:1; from about1:1.3 to about 1.3:1 or from about 1:1.1 to about 1.1:11.

Active Agents

In certain embodiments, any of the following active agents can be usedin the solid oral dosage form of the present invention: ACE inhibitors,adenohypophoseal hormones, adrenergic neuron blocking agents,adrenocortical steroids, inhibitors of the biosynthesis ofadrenocortical steroids, alpha-adrenergic agonists, alpha-adrenergicantagonists, selective alpha-two-adrenergic agonists, analgesics,anti-pyretics, anti-inflammatory agents, androgens, local and generalanesthetics, anti-addictive agents, anti-androgens, anti-arrhythmicagents, anti-asthmatic agents, anti-cholinergic agents,anti-cholinesterase agents, anti-coagulants, anti-diabetic agents,anti-diarrheal agents, anti-diuretic, anti-emetic agents, pro-kineticagents, anti-epileptic agents, anti-estrogens, anti-fungal agents,anti-hypertensive agents, anti-microbial agents, anti-migraine agents,anti-muscarinic agents, anti-neoplastic agents, anti-parasitic agents,anti-Parkinson's agents, anti-platelet agents, anti-progestins,anti-schizophrenia agents, anti-thyroid agents, anti-tussives,anti-viral agents, atypical anti-depressants, azaspirodecanediones,barbiturates, benzodiazepines, benzothiadiazides, beta-adrenergicagonists, beta-adrenergic antagonists, selective beta-one-adrenergicantagonists, selective beta-two-adrenergic agonists, bile salts, agentsaffecting volume and composition of body fluids, butyrophenones, agentsaffecting calcification, calcium channel blockers, cardiovascular drugs,cannabinoids, catecholamines and sympathomimetic drugs, cholinergicagonists, cholinesterase reactivators, contraceptive agents,dermatological agents, diphenylbutylpiperidines, diuretics, ergotalkaloids, estrogens, ganglionic blocking agents, ganglionic stimulatingagents, hydantoins, agents for control of gastric acidity and treatmentof peptic ulcers, hematopoietic agents, histamines, histamineantagonists, hormones, 5-hydroxytryptamine antagonists, drugs for thetreatment of hyperlipoproteinemia, hypnotics, sedatives,immunosupressive agents, laxatives, methylxanthines, moncamine oxidaseinhibitors, neuromuscular blocking agents, organic nitrates, opioidagonists, opioid antagonists, pancreatic enzymes, phenothiazines,progestins, prostaglandins, agents for the treatment of psychiatricdisorders, psychotropics, retinoids, sodium channel blockers, agents forspasticity and acute muscle spasms, succinimides, testosterones,thioxanthines, thrombolytic agents, thyroid agents, tricyclicantidepressants, inhibitors of tubular transport of organic compounds,drugs affecting uterine motility, vasodilators, vitamins, and mixturesthereof.

In certain embodiments, the active agent is a drug susceptible to abuse(e.g., an opioid agonist). In such embodiments, the opioid agonist isselected from the group consisting of alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine,butorphanol, clonitazene, codeine, desomorphine, dextromoramide,dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine,dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone,hydromorphone, hydroxypethidine, isomethadone, ketobemidone,levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol,metazocine, methadone, metopon, morphine, myrophine, nalbuphine,narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum,pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine,piminodine, piritramide, proheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tilidine, tramadol, pharmaceuticallyacceptable salts thereof, and mixtures thereof. In certain embodiments,the opioid agonist is selected from the group consisting of codeine,fentanyl, hydromorphone, hydrocodone, oxycodone, dihydrocodeine,dihydromorphine, morphine, tapentadol, tramadol, oxymorphone,pharmaceutically acceptable salts thereof, and mixtures thereof.

In certain embodiments, the opioid agonist is oxycodone or apharmaceutically acceptable salt thereof (e.g., oxycodone hydrochloride)in an amount, e.g., from about 2.5 mg to about 320 mg, or in an amountof about 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg,60 mg, 80 mg, 120 mg, 160 mg or 320 mg.

In certain embodiments of the present invention, wherein the activeagent is oxycodone hydrochloride, the oxycodone hydrochloride has a14-hydroxycodeinone level of less than about 25 ppm, less than about 15ppm, less than about 10 ppm, less than about 5 ppm, less than about 2ppm, less than about 1 ppm, less than about 0.5 ppm or less than about0.25 ppm.

WO 2005/097801 A1, U.S. Pat. No. 7,129,248 B2 and US 2006/0173029 A1,all of which are hereby incorporated by reference, describe a processfor preparing oxycodone hydrochloride having reduced levels of14-hydroxycodeinone.

In certain embodiments, the opioid agonist is morphine or apharmaceutically acceptable salt thereof (e.g., morphine sulfate) in anamount, e.g., of from about 15 mg to about 200 mg, or in an amount ofabout 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100mg, 120 mg, 150 mg or 200 mg.

In embodiments in which the opioid analgesic comprises hydrocodone,dosage forms may include analgesic doses from about 2 mg to about 50 mgof hydrocodone bitartrate. In embodiments in which the opioid analgesiccomprises hydromorphone the dosage form may include from about 2 mg toabout 64 mg hydromorphone hydrochloride.

The solid oral dosage forms of the present invention can provide acontrolled release of the active agent. Certain embodiments can alsoprovide a first portion of the active agent for immediate release and asecond portion of the active agent for controlled release. For example,an immediate release portion of the drug can be layered over theparticles of the dosage form or can be included in additional tabletexcipients of which the particles are embedded.

In certain embodiments, the solid oral dosage form of the presentinvention comprises an active agent that is an opioid antagonist (withor without an opioid agonist). In such embodiments, the opioidantagonist is selected from the group consisting of amiphenazole,naltrexone, methylnaltrexone, naloxone, nalbuphine, nalorphine,nalorphine dinicotinate, nalmefene, nadide, levallorphan, cyclozocine,pharmaceutically acceptable salts thereof and mixtures thereof.

In certain embodiments, the solid oral dosage form of the presentinvention comprises an active agent that is a non-opioid analgesic. Insuch embodiments, the non-opioid analgesic is a non-steroidalanti-inflammatory agent selected from the group consisting of aspirin,celecoxib, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen,fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen,oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen,tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac,tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac,clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid,niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam,sudoxicam, isoxicam, pharmaceutically acceptable salts thereof andmixtures thereof.

In other embodiments, the present invention is directed to the dosageforms disclosed herein utilizing active agents such as benzodiazepines,barbiturates or amphetamines, their antagonists, or combinationsthereof.

Benzodiazepines to be used in the present invention may be selected fromalprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam,estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam,oxazepam, prazepam, quazepam, temazepam, triazolam, and pharmaceuticallyacceptable salts, hydrates, and solvates and mixtures thereof.Benzodiazepine antagonists that can be used in the present inventioninclude, but are not limited to, flumazenil and pharmaceuticallyacceptable salts, hydrates, and solvates.

Barbiturates to be used in the present invention include, but are notlimited to, amobarbital, aprobarbotal, butabarbital, butalbital,methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital,secobarbital and pharmaceutically acceptable salts, hydrates, andsolvates mixtures thereof. Barbiturate antagonists that can be used inthe present invention include, but are not limited to, amphetamines andpharmaceutically acceptable salts, hydrates, and solvates.

Stimulants to be used in the present invention include, but are notlimited to, amphetamines, such as amphetamine, dextroamphetamine resincomplex, dextroamphetamine, methamphetamine, methylphenidate andpharmaceutically acceptable salts, hydrates, and solvates and mixturesthereof. Stimulant antagonists that can be used in the present inventioninclude, but are not limited to, benzodiazepines, and pharmaceuticallyacceptable salts, hydrates, and solvates as described herein.

Certain embodiments contain more than one active agent. For example, thedosage forms disclosed herein can contain both an opioid agonist and anon-opioid analgesic. In particular embodiments, the non-opioidanalgesic is acetaminophen or a non-steroidal anti-inflammatory agent(e.g., ibuprofen, aspirin or diclofenac) and the opioid agonist isoxycodone, hydrocodone or pharmaceutically acceptable salts thereof(e.g., oxycodone hydrochloride or hydrocodone bitratrate).

The following examples are set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention described and claimed herein. Such variations of theinvention, including the substitution of all equivalents now known orlater developed, which would be within the purview of those skilled inthe art, and changes in formulation or minor changes in experimentaldesign, are to be considered to fall within the scope of the inventionincorporated herein.

EXAMPLES Example 1A

Preparation of Oxycodone-Eudragit® NE Granules

Oxycodone HCl-Eudragit® NE granules were prepared with various additivesto determine the effect the additives have on the adherence of neutralacrylic polymer (Eudragit® NE) (NE) to Oxycodone HCl. In this and all ofthe following Examples, the neutral acrylic polymer used is Eudragit® NE40 D.

Oxycodone HCl was granulated with low viscosityhydroxypropylmethylcellulose (HPMC E5), Nonoxynol 9 or carbomer(Carbopol® 71G) in a high shear granulator to form seed granules. TheseOxycodone HCl seed granules were screened then furthergranulated/layered with Eudragit® NE dispersion containingmethylcellulose having a viscosity of 1,500 cPs in 2% solution (MC A15C)in a rotor-granulator, followed by drying in the rotor-granulator. Theratios of the ingredients (by weight) are shown in Table 1A below.

TABLE 1A Components % Oxycodone HCl 5.8 5.5 5.3 5.5 Eudragit ® NE 93.793.7 93.7 93.7 Methyl Cellulose A15C 0.5 0.5 0.5 0.5 HPMC E5 0 0.3 0 0Nonoxynol 9 0 0 0.5 0 Carbopol ® 71G 0 0 0 0.3

The granules were then tested for dissolution after tampering, and theresults for Oxycodone-Eudragit® NE granules with no additives,Oxycodone-Eudragit® NE granules with HPMC E5, Oxycodone-Eudragit® NEgranules with Nonoxynol 9 and Oxycodone-Eudragit® NE granules withCarbopol® 71G are shown in FIGS. 1A, 1B, 1C and 1D, respectively.

Example 1B

Preparation of Oxycodone-NE Granules with Lactose

Since the Oxycodone HCl-Eudragit® NE granules with Carbopol® 71Gexhibited the best tamper resistance, Oxycodone-NE granules withCarbopol® 71G were prepared in accordance with Example 1A, with varyingamounts of Oxycodone HCl, methylcellulose having a viscosity of 40,000cPs in 2% solution (MC A40M), Eudragit® NE and lactose monohydrate todetermine the effects on dissolution in SGF. The compositions ofcomponents (weight %) of the various formulations prepared are shown inTable 1B below.

TABLE 1B Components % % % Internal Oxycodone HCl 5.9 5.8 44.2 CoreCarbopol ® 71G 0.3 2.1 2.2 MC A40M 37.0 36.3 0 NE Eudragit ® NE 54.151.9 48.7 Layer Lactose monohydrate 2.7 3.9 4.9

Dissolution was then tested, and the results are shown in FIG. 2. Asshown, in the absence of internal MC A40M, higher levels of lactose (10%relative to NE) were not able to increase dissolution rate fromOxycodone-NE granules. However, the presence of internal MC A40M had anenhancing effect on the dissolution rate of the Oxycodone-NE granules.

Example 1C

Oxycodone HCl:Eudragit® NE Ratio

Oxycodone HCl-Eudragit® NE granules were prepared in accordance withExample 1A, with varying amounts of components to determine therelationship between particle size and resistance to milling. Particlesizes greater than 600 μm and less than 600 μm were prepared. Thecompositions of components (weight %) in the various formulationsprepared are shown in Table 1C below.

TABLE 1C Particle Particle >600 μm <600 μm ~80% of all ~20% of allparticles particles Components % % Internal Oxycodone HCl 5.9 1.5 coreCarbopol ® 71G 0.3 0.1 MC A40M 37.0 9.5 NE Eudragit ® NE 54.1 84.7 layerLactose monohydrate 2.7 4.2

Dissolution was then tested, and the results for granules greater than600 μm and less than 600 μm are shown in FIGS. 3A and 3B, respectively.As shown, the smaller sized granules had higher Eudragit® NE loading,and better resistance to milling.

Next, the formulations were varied to test the effects of the amounts ofCarbopol® 71G and lactose monohydrate on the formulation. Thecompositions of components (weight %) in the various formulationsprepared are shown in Table 1D below.

TABLE 1D Particle Particle >600 μm <600 μm ~52% of all ~48% of allparticles particles Components % % Internal Oxycodone HCl 5.8 3.4 coreCarbopol ® 71G 2.1 1.3 MC A40M 36.3 21.6 NE Eudragit ® NE 51.9 68.6layer Lactose monohydrate 3.9 5.1

Dissolutions were then tested, and the results for granules greater than600 μm and less than 600 μm are shown in FIGS. 4A and 4B, respectively.As shown, increasing levels of Carbopol® 71G and lactose monohydrateimproved granule particle size and Eudragit® NE coating uniformity.Similar to Example 1C, the smaller sized granules had higher Eudragit®NE loading, and better resistance to milling.

The Oxycodone HCl-Eudragit® NE granules with Carbopol® 71G having aparticle size of less than 600 μm were then tested for alcoholresistance in 40% EtOH/SGF. The results are shown in FIG. 5. As shown,the Oxycodone HCl-Eudragit® granules were not alcohol resistant.

Example 1D

Film Coating

In an attempt to improve alcohol resistance, the Oxycodone HCl-Eudragit®NE granules with Carbopol® 71G of Example 1C were coated with anexternal layer of methylcellulose (MC A15LV). The compositions of thecomponents (weight %) of the formulation are shown in Table 1E below.

TABLE 1E Components % Internal Oxycodone HCl 3.2 Carbopol ® 71G 1.2 MCA40M 20.4 NE Eudragit ® NE 65.5 Layer Lactose monohydrate 4.9 ExternalMC A 15LV 4.8 Layer

This formulation was then tested for alcohol resistance and the datacompared with the formulation without the external MC layer, as shown inFIG. 6. As shown, the addition of the 4.8% film coating of MC A15LV didnot improve alcohol resistance.

Example 1E

Granulation with External Excipients

The formulation was then modified to replace the external coat of MCA15LV by wet granulation with extra-granular MCA40M (granulated withwater). The compositions (weight %) of formulations, as compared to theformulation without the extra-granular MC A40M, are shown in Table 1Fbelow.

TABLE 1F Core Oxycodone- Low Ext. High Ext. NE MCA40M MCA40M Components% % % Internal Oxycodone HCl 3.4 1.7 1.1 Carbopol ® 71G 1.3 0.6 0.4 MCA40M 21.6 10.8 7.2 NE Eudragit ® NE 68.6 34.6 23.1 Layer Lactosemonohydrate 5.1 2.6 1.7 External MC A40M 0 49.7 66.5 Layer

The formulations with extra-granular MC A40M were then tested foralcohol resistance, and the results are shown in FIG. 7. As shown, therewas no improvement on alcohol resistance.

Next, Carbopol® 71G was added to the extra-granular layer in the amounts(by weight) shown in Table 1G below.

TABLE 1G External External MC A40M MC A40M granulated granulated Corewithout with Oxycodone- Carbopol ® Carbopol ® NE 71G 71G Components % %% Internal Oxycodone HCl 3.4 1.7 2.6 Carbopol ® 71G 1.3 0.6 0.9 MC A40M21.6 10.8 16.3 NE Eudragit ® NE 68.6 34.6 52.4 Layer Lactose 5.1 2.6 3.9monohydrate External MCA40M 0 49.7 19.0 Layer Carbopol ® 71G 0 0 4.9

Oxycodone HCl-Eudragit® NE granules were prepared with various levels ofadditives to determine the effect the additives have on the adherence ofEudragit® NE to MC A40M and consequently on alcohol resistance

The extra-granular MCA40M/Carbopol® 71G formulation was then tested foralcohol resistance, and the results are shown in FIG. 8. As shown, thegranulation of external MC A40M with Carbopol® 71G solution as a binderimproved binding and adhesion of the external MC A40M to the Eudragit®NE, thereby improving the alcohol resistance.

To determine the effect of the amount of Carbopol® 71G on alcoholresistance, the amount of Carbopol® 71G was doubled, as shown in Table1H below.

TABLE 1H Oxycodone- Oxycodone- Core NE-MC NE-MC Oxycodone- (lower level(higher level NE of ext. of ext. granules MCA40M) MCA40M) Components % %% Internal Oxycodone HCl 3.4 2.6 2.1 Carbopol ® 71G 1.3 0.9 0.8 MC A40M21.6 16.3 13.2 NE Eudragit ® NE 68.6 52.4 42.2 Layer Lactose 5.1 3.9 3.2External MCA40M 0 19.0 30.7 Layer Carbopol ® 71G 0 4.9 7.8

The extra-granular MCA40M/Carbopol® 71G formulation was then tested foralcohol resistance, and the results are shown in FIG. 9. As shown,increased amount of Carbopol® 71G did not improve alcohol resistance.

The dissolution of 4.9% Carbopol® 71G (external layer) formulation wasthen tested in 900 ml SGF, and the results are shown in FIG. 10. Asshown, the external layer of MC/Carbopol® 71G also helps to increase thedissolution in SGF.

The formulation was then tested for resistance to milling, and theresults are shown in FIG. 11. As shown, the external layer ofMC/Carbopol® 71G did not compromise the resistance of the granules tomilling.

Example 2

10 mg Oxycodone HCl-Eudragit® NE Tablet Preparation

Tablet formulations were prepared as follows:

Internal Core—Stage 1

Equipment

Vector GMX Micro High-Shear granulator

Glatt® Fluid Bed Dryer—Model Versa Glatt

Comil® Comminuting Mill

Stainless Steel Screens—US Std. #18, #30

Procedure

-   -   1. A 4% w/w binder solution of Carbopol® 71G in 0.1 N HCl was        prepared.    -   2. Carbopol® 71G in the internal core was added in two parts.        60% of the Carbopol® 71G was added dry with Oxycodone HCl and        methyl cellulose (MCA40M) in the granulator. Remainder 40%        Carbopol® 71G was added as the binder solution (Step 1).    -   3. The ingredients for the internal core—oxycodone HCl, methyl        cellulose A40M (MC) and Carbopol® 71G were charged into the bowl        of high-shear granulator (impeller speed 300 rpm, chopper speed        300 rpm) and dry mixed for 1 minute.    -   4. The mixture from step 3 was granulated with Carbopol® 71G        binder solution (from step 1) which was sprayed at 20 g/min    -   5. If required, additional water was sprayed during granulation        to obtain a cohesive free flowing mass.    -   6. The wet granulations were milled through Comil® fitted with        mesh #18 (1000 micron opening) screen.    -   7. The wet milled granulations were dried in a fluid bed dryer        at inlet temperature of 45° C., and an air volume adjusted to        fluidize the bed. The moisture content of the dried granulations        was <5%.    -   8. The dried granulations were milled through Comil® fitted with        mesh #30 (600 micron opening) screen.

Eudragit® NE Layer—Stage 2

Equipment

Vector VFC-Lab3 Ho-Coater with GXR-35 rotor—also called Rotor-granulator

Stainless Steel Screen—US Std. #30

Hotpack Tray Dryer

Procedure

-   -   1. Binder solution was prepared by mixing Eudragit® NE        dispersion (27.9% Eudragit® NE solids) and lactose monohydrate        (2.1%) to obtain total solids content of 30% w/w in the        dispersion.    -   2. The milled internal core granulations from Step 8/stage 1        were charged into the chamber of the rotor-granulator.    -   3. The rotor was operated at plate speed=300 rpm, slit airflow=8        cfm, and inlet/slit temperature=25° C.    -   4. Water was sprayed at a rate of 3.5 g/min until product        temperature was below 16° C.    -   5. When the product temperature was less than 16° C., Eudragit®        NE-Lactose monohydrate dispersion spray was begun at 3.5 g/min.    -   6. The product temperature was monitored and controlled such        that it stayed between 14-16° C. The product temperature was        controlled by adjusting binder spray rate, slit airflow, and        slit temperature.    -   7. Granule samples were collected at various levels of Eudragit®        NE loading for testing. The granule samples were screened        through mesh #30 screen, cured in a tray dryer at 60° C. for 24        hours, and tested for drug release from intact and        milled/crushed granules.    -   8. The end point of Eudragit® NE-Lactose layering was determined        by dissolution results from step 7, i.e. dissolution profiles in        SGF from intact and milled/crushed granules were similar. When        the end-point was reached, Eudragit® NE-Lactose dispersion        spraying was stopped.    -   9. The granules were dried in the rotor at 25° C. till a        moisture content of less than 5% was obtained.    -   10. The granules were discharged from the rotor and screened        through sieve #30 (opening 600 microns).    -   11. The granules which passed through sieve #30 were cured in a        tray dryer at 60° C. for 24 hours.

External Layer—Stage 3

Equipment

Vector GMX Micro High-Shear granulator

Glatt® Fluid Bed Dryer—Model Versa Glatt

Comil® Comminuting Mill

Stainless Steel Screens—US Std. #18

Procedure

-   -   1. A 4% w/w binder solution of Carbopol® 71G in 0.1 N HCl was        prepared.    -   2. Carbopol® 71G in the external layer was added in two parts.        60% of the Carbopol® 71G was added dry with cured, screened        granules from Step 11/stage 2 and methyl cellulose A40M (MC        A40M) in the granulator. Remainder 40% of Carbopol® 71G was        added as the binder solution (step 1).    -   3. The ingredients for the external layering—cured, screened        granules from Step 11/stage 2, methyl cellulose A40M (MC A40M)        and Carbopol® 71G were charged into the bowl of high-shear        granulator (impeller speed 300 rpm, chopper speed 300 rpm) and        dry mixed for 1 minute.    -   4. The mixture from step 3 was granulated with Carbopol® 71G        binder solution (from step 1) which was sprayed at 20 g/min    -   5. If required, additional water was sprayed during granulation        to obtain a cohesive free flowing mass.    -   6. The wet granulations were milled through Comil® fitted with        mesh #18 (1000 micron opening) screen.    -   7. The wet milled granulations were dried in a fluid bed dryer        at inlet temperature of 45° C., and an air volume adjusted to        fluidize the bed. The moisture content of the dried granulations        was less than 5%.    -   8. The dried granulations were milled through Comil® fitted with        mesh #18 (1000 micron opening) screen, and compressed into        tablets

The compositions (weight %) of the components in the tablet formulationare shown in Table 2 below.

TABLE 2 Components % Internal Oxycodone HCl 2.6 Core Carbopol ® 71G 0.9MC A40M 16.3 NE Eudragit ® NE 52.4 Layer Lactose monohydrate 3.9External MC A40M 19.0 Layer Carbopol ® 71G 4.9

Dissolution of the prepared tablets was performed as follows:

-   -   1. Apparatus USP Type 2, paddles, 50 rpm at 37° C.    -   2. Sampling time—every 30 minutes up to 720 minutes.    -   3. Media—900 ml simulated gastric fluid (SGF, pH 1.2), or        Simulated gastric fluid+Ethanol (60:40 v/v)    -   4. Analytical method—UV analysis, Distek Fiber Optic Dissolution        System (Distek Opt-Diss 405) at wavelength 280 nm, double        wavelength correction.

Assay

-   -   1. Sample diluted with simulated gastric fluid (SGF, pH 1.2)    -   2. Analytical method—UV analysis, Distek Fiber Optic Dissolution        System (Distek Opt-Diss 405) at wavelength 280 nm, double        wavelength correction.

Milling

-   -   1. 1 dose was added to the chamber of Krups coffee mill and        milled for 15 sec, switching off for 10 sec. This procedure was        repeated 3 more times for a total milling time of 60 sec.    -   2. Dissolution testing of milled samples in SGF was performed as        described in “Dissolution” above.

Crushing

-   -   1. 1 dose was added to a glass mortar and triturated/crushed        with pestle continuously for 2 minutes.    -   2. Dissolution testing of crushed samples in SGF was performed        as described in “Dissolution” above.

The dissolution profiles of the tablet formulation, intact in SGF andcrushed and milled in SGF are shown in FIG. 12A. The dissolutionprofiles of the intact tablet in alcohol/SGF and SGF, are shown in FIG.12B.

Example 3

10 mg Oxycodone HCl-Eudragit® NE Tablet Small Volume Extraction &Syringability Studies

The tablets of Example 2 were tested for extractability by small volumeof various solvents at various temperatures. The studies were performedas follows:

Small Volume Extraction:

-   -   1. One dose of sample was milled in Krups coffee mill and        transferred to a 60-ml glass vial with plastic closure.    -   2. 30 ml solvent was added to the vial and shaken in a water        bath shaker at room and elevated temperatures (50° C. for        organic solvents, 95° C. for aqueous solvents).    -   3. Aliquots of sample (5.0 mL) were removed at 10 and 60 min,        diluted, filtered and assayed for drug content.        List of Extraction Solvents        Water, pH 3 buffer, pH 10 buffer, 40% Ethanol, Cooking Oil

The results after 10 minutes and 60 minutes are shown in FIGS. 13A and13B, respectively.

Syringability:

Room Temperature Samples

-   -   1. One dose of sample was milled in Krups coffee mill, added to        a vial with 5 or 10 ml distilled water and shaken by hand for 30        seconds.    -   2. Using a 18, 22, 25 or 27 gauge needle fitted on a 5 or 10 mL        syringe, attempt was made to aspirate as much liquid as possible        during a 5-minute time period. For the 10 minute time        point—sample was allowed to stay in vial for 10 minutes before        attempting to syringe.    -   3. The amount of drug extracted was assayed.        Heated Samples    -   1. One dose of sample was milled in Krups coffee mill, added to        a vial with 5 ml distilled water. The sample was heated in vial        with a butane lighter and shaken by hand for 30 seconds.    -   2. Using a 18, 22, 25 or 27 gauge needle fitted on a 5 or 10 mL        syringe, attempt was made to aspirate as much liquid as possible        during a 5-minute time period. For the 10 minute time        point—sample was allowed to stay in vial for 10 minutes before        attempting to syringe.    -   3. The amount of drug extracted was assayed.        The results are shown in FIG. 14

Example 4A

15 mg Morphine Sulfate-Eudragit® NE Tablet Preparation

The subject tablet formulations were prepared with the composition(weight %) of components as shown in Table 4A below, using the equipmentand procedures referred to in Example 2.

TABLE 4A Components % (by weight) Internal Morphine Sulfate 4.2 CoreCarbopol ® 71G 1.1 MC A40M 17.1 NE Layer Eudragit ® NE 48.7 Lactosemonohydrate 3.7 External MC A40M 21.5 Layer Carbopol ® 71G 3.3 MagnesiumStearate 0.5

The tablet of Example 4A was subject to milling and dissolutionaccording to the protocols in Example 2. The dissolution of a milledtablet formulation, an intact tablet formulation, milled final granulesand intact final granules in 900 mL SGF is shown in FIG. 15A. Thedissolution of an intact tablet formulation in 900 mL SGF and an intacttablet formulation in 900 mL of 40% alcohol/SGF is shown in FIG. 15B.

Example 4B

10 mg Oxycodone/5 mg Naloxone NE/MC Tablet Preparation

The subject tablet formulations were prepared with the composition(weight %) of components as shown in Table 4B below, using the equipmentand procedures referred to in Example 2.

TABLE 4B Components % (by weight) Internal Oxycodone HCl 2.5 CoreNaloxone HCl 1.4 Carbopol ® 71G 1.0 MC A40M 15.0 NE Eudragit ® NE 52.2Layer Lactose monohydrate 3.9 External MC A40M 18.9 Layer Carbopol ® 71G4.9 Magnesium Stearate 0.2

The tablet of Example 4B was subject to milling and dissolutionaccording to the protocols in Example 2. The dissolution of milled finalgranules, intact final granules, a milled tablet formulation and anintact tablet formulation in 900 mL SGF is shown in FIG. 16.

Example 4C

Preparation of 200 mg Morphine Sulfate-Eudragit® NE Granules withDifferent Internal Fillers

The subject granules were prepared with the compositions of components(weight %) as shown in Table 4C below, using the equipment andprocedures referred to in Example 2 (excluding Stage 3).

TABLE 4C MC MC A40M Ac-Di-Sol A40M as Ac-Di-Sol as As internal asinternal internal filler internal filler filler (higher filler (higher(low NE) NE) (low NE) NE) % (by % (by % (by % (by Components weight)weight) weight) weight) Internal Morphine 25.1 15.8 27.7 16.5 CoreSulfate Carbopol ® 3.8 2.4 6.2 3.7 71G MC A40M 25.1 15.8 0 0 Ac-Di-Sol 00 13.9 8.3 NE Eudragit ® 42.7 61.5 48.5 66.5 Layer NE Lactose 3.2 4.63.6 5.0 monohydrate

The granules of Example 4C were subjected to milling and dissolutionaccording to the protocols in Example 2. The dissolution of milled andintact final granules with croscarmellose sodium (Ac-Di-Sol®) and lowEudragit® NE, milled and intact final granules with MC A40M and lowEudragit® NE, milled and intact final granules with Ac-Di-Sol and highEudragit® NE, and milled and intact final granules with MC A40M and highEudragit® NE in 900 mL SGF is shown in FIG. 17.

Example 5A

15 mg Morphine Sulfate NE/MC Tablet Small Volume Extraction &Syringability Studies

Using the equipment and procedures referred to in Example 3, tabletsaccording to Example 4A were tested for syringability and extractabilityby small volume of various solvents at various temperatures. The resultsare shown in FIG. 18A (water at room temperature and boiling) and 18B(40% ethanol at 50° C. and 95° C.).

Example 5B

10 mg Oxycodone/5 mg Naloxone NE/MC Tablet Small Volume Extraction &Syringability Studies

Using the equipment and procedures referred to in Example 3, tabletsaccording to Example 4B were tested for syringability and extractabilityby small volume of various solvents at various temperatures. The resultsare shown in FIG. 19A (water at room temperature and boiling) and 19B(water and 40% ethanol at various temperatures).

Example 5C

200 mg Morphine Sulfate NE Granulations with Different Internal FillersGranules Small Volume Extraction & Syringability Studies

Using the equipment and procedures referred to in Example 3, tabletsaccording to Example 4C were tested for syringability and extractabilityby small volume of various solvents at various temperatures. The resultsare shown in FIG. 20A (water at room temperature and boiling) and 20B(water at 25 and 95° C.).

Example 6A

Preparation of 200 mg Morphine-Eudragit® NE Formulations using DifferentPore Formers

Procedure:

Internal Core—Stage 1

Equipment

Vector GMX Micro High-Shear granulator

Vector Fluid bed dryer

Comil® Comminuting Mill

Stainless Steel Screens—US Std. #18, #30

Procedure

-   -   1. A 4% w/w binder solution of Carbopol® 71G in 0.1 N HCl was        prepared.    -   2. Carbopol® 71G in the internal core was added in two parts.        50% of the Carbopol® 71G was added dry with morphine sulfate and        methyl cellulose A40M (MCA40M) in the granulator. Remainder 50%        Carbopol® 71G was added as the binder solution (from step 1).    -   3. The ingredients for the internal core—morphine sulfate,        methyl cellulose A40M (MC A40M) and Carbopol® 71G were charged        into the bowl of high-shear granulator (impeller speed 300 rpm,        chopper speed 300 rpm) and dry mixed for 1 minute.    -   4. The mixture from step 3 was granulated with Carbopol® 71G        binder solution (from step 1) which was sprayed at 40 g/min    -   5. If required, additional water was sprayed during granulation        to obtain a cohesive free flowing mass.    -   6. The wet granulations were milled through Comil® fitted with        mesh #18 (1000 micron opening) screen.    -   7. The wet milled granulations were dried in a fluid bed dryer        at inlet temperature of 40° C., and an air volume adjusted to        fluidize the bed. The moisture content of the dried granulations        was <5%.    -   8. The dried granulations were milled through Comil® fitted with        mesh #30 (600 micron opening) screen.        The composition (weight %) of the internal core is shown in        Table 6A.1 below.

TABLE 6A.1 Components % (by weight) Internal core Morphine Sulfate 46.5Carbopol ® 71G 7.0 MC A40M 46.5Eudragit® NE layer—Stage 2

Equipment: 100 mL food processor

Procedure:

Binder solutions were prepared by mixing Eudragit® NE dispersion anddifferent pore formers, the compositions are shown in the Table 6A.2below.

TABLE 6A.2 Eudragit ® NE solid Pore Former Pore former concentration (%)concentration (%) Lactose monohydrate 38.8 2.91 PEG 400 38.5 3.85 PEG4000 38.5 3.85 Propylene glycol 38.5 3.85 NaCl 37.0 7.41 NaCl 38.5 3.85HPMC E6 34.9 1.75 Sodium CMC 39.2 1.96 SiO₂ 39.2 1.96

-   -   1. The milled internal core granulations from Step 8/stage 1        were charged into the 100 mL food processor.    -   2. The binder solution was added slowly into the food processor        to granulate the materials from step 1.    -   3. Wet granules from step 2 were dried in a vacuum oven at 60°        C.    -   4. The dried granules from step 3 were recharged to the food        processor; steps 2 and 3 were repeated until desired weight gain        was reached.    -   5. The final coated granules were passed through sieve #30, and        cured in a tray dryer at 60° C. for 24 hours.    -   6. Intact cured granules were tested for drug release in 900 mL        Simulated Gastric Fluid (SGF) using the test method of Example        2.

FIG. 21 shows the results of the dissolution tests of the formulationsof Example 6A for each of the pore formers.

Example 6B

Preparation of 200 mg Morphine-Eudragit® NE Granule Formulations UsingHPMC as a Pore Former

The subject formulations were prepared with the compositions (weight %)of components as shown in Table 6B below, using the equipment andprocedures referred to in Example 2 (excluding Stage 3).

TABLE 6B Intermediate Low NE NE Higher NE % % % Components (by weight)(by weight) (by weight) Internal Morphine 24.4 19.0 15.6 core SulfateCarbopol ® 24.4 19.0 15.6 71G MC A40M 5.5 4.3 3.5 NE Eudragit ® 43.555.0 62.3 Layer NE HPMC E6 2.2 2.7 3.1

The granules of Example 6B were subject to milling, crushing anddissolution according to the protocols in Example 2. The dissolution ofmilled, crushed and intact final granules with low Eudragit® NE, milled,crushed and intact final granules with intermediate Eudragit® NE andmilled, crushed and intact final granules with high Eudragit® NE in 900mL SGF is shown in FIG. 22.

Example 6C

Preparation of 200 mg Morphine-Eudragit® NE Granule Formulations UsingNaCl as a Pore Former

The subject formulations were prepared with the compositions (weight %)of components as shown in Table 6C below, using the equipment andprocedures referred to in Example 2 (excluding Stage 3).

TABLE 6C Intermediate Low NE NE Higher NE % % % Components (by weight)(by weight) (by weight) Internal Morphine Sulfate 24.4 19.0 15.6 coreCarbopol ® 71G 24.4 19.0 15.6 MC A40M 5.5 4.3 3.5 NE Eudragit ® NE 43.555.0 62.3 Layer NaCl 2.2 2.7 3.1

The granules of Example 6C were subject to milling, crushing anddissolution according to the protocols in Example 2. The dissolution ofmilled, crushed and intact final granules with low Eudragit® NE, milled,crushed and intact final granules with intermediate Eudragit® NE andmilled, crushed and intact final granules with high Eudragit® NE in 900mL SGF is shown in FIG. 23.

Example 6D

Small Volume Extraction & Syringability Studies of 200 mg Morphine NEGranule Formulations using NaCl as Pore Former

Using the equipment and procedures referred to in Example 3, granulesfrom Example 6D were tested for syringability and extractability bysmall volume of various solvents at various temperatures. The resultsare shown in FIG. 24A (water at room temperature and boiling) and 24B(water at various temperatures).

Example 7

15 mg Naloxone HCl.2H₂O—NE Core Granule Preparation

Core granule formulations were prepared as follows:

Internal Core—Stage 1

Equipment

10 L Collette High-Shear granulator

Vector VFC3 Fluid Bed Dryer

Comil® Comminuting Mill

Stainless Steel Screens—1016 μm, 813 μm, 595 μm

Procedure

-   -   1. A 4% w/w binder solution of Carbopol® 71G in 0.1 N HCl was        prepared.    -   2. Carbopol® 71G in the internal core was added in two parts.        50%˜70% of the Carbopol® 71G was added dry with Naloxone        HCl.2H₂O and methyl cellulose (MCA40M) into the granulator.        Remainder 30˜50% of Carbopol® 71G was added as the binder        solution (Step 1).    -   3. The ingredients of the internal core—naloxone HCl. 2H₂O,        methyl cellulose A40M (MC) and Carbopol® 71G (dry) were charged        into the bowl of high-shear granulator (impeller speed 300 rpm,        chopper speed 300 rpm) and dry mixed for 1 minute.    -   4. The mixture from step 3 was granulated with Carbopol® 71G        solution which was sprayed at 60 g/min    -   5. If required additional water was sprayed during granulation        to obtain a cohesive free flowing mass.    -   6. The wet granulations were milled through Comil® fitted with        1016 μm opening screen.    -   7. The wet milled granulations were dried in a fluid bed dryer        at inlet temperature of 40° C., at an air volume adjusted to        fluidize the bed. The moisture content of the dried granulation        was <5%.    -   8. The dried granulations were first milled through Comil®        fitted with 1016 μm opening screen, and then the materials        larger than 595 μm were milled through Comil® fitted with 813 μm        opening screen.

Eudragit® NE Layer—Stage 2

Equipment

Solidlab II

Stainless Steel Screen—US Std. #14

Hotpack Tray Dryer

Procedure

-   -   1. Binder solution was prepared by mixing Eudragit® NE 40D        dispersion and lactose monohydrate (weight ratio of solid        Eudragit® NE and lactose is 1/0.075) to obtain total solids        content of 41.75% w/w in the dispersion.    -   2. After Solidlab II was preheated to around 25° C., the        internal core granulation from Step 9/stage 1 was charged into        the chamber of Solidlab II.    -   3. When the product temperature was 20° C., Eudragit® NE-lactose        dispersion prepared in step 1/stage 2 was sprayed at spray        rate=10-38 g/min, inlet airflow=150-300 m³/hr, inlet air        temperature=20-40° C., product temperature=20° C., inlet air        relative humidity=0%.    -   4. The product temperature was monitored and controlled by        adjusting binder spray rate, inlet airflow, and inlet air        temperature.    -   5. Granule samples were collected at various levels of Eudragit®        NE loading for testing. When 440% weight gain was obtained, the        coating was stopped.    -   6. After the collected granule samples were dried in the oven at        25° C., the granules were cured in a tray dryer at 60° C. for 24        hours.    -   7. The cured granules were de-agglomerated through #14 mesh        screen.    -   8. Dissolution was tested on the milled and intact cured        granules from step 7/stage2        The composition of the core granulations is shown in the Table 7        below.

TABLE 7 Components % Internal Naloxone HCl•2H₂O 9.6 Core Carbopol ® 71G2.4 MC A40M 36.0 NE Eudragit ® NE 48.4 Layer Lactose monohydrate 3.6Dissolution of the core granules was performed as follows:

-   -   1. Apparatus USP Type 2, paddles, 50 rpm at 37° C.    -   2. Media—900 ml simulated gastric fluid (SGF, pH 1.2)    -   3. Analytical method—UV analysis, Distek Fiber Optic Dissolution        System (Distek Opt-Diss 405) at wavelength 280 nm, double        wavelength correction.        Milling    -   1. One dose was added to the chamber of Krups coffee mill and        milled for 15 sec, switching off for 10 sec. This procedure was        repeated 3 more times for a total milling time of 60 sec.    -   2. Dissolution testing of milled samples in SGF was performed as        described in “Dissolution” above.        The dissolution profiles of the intact and milled core        granulations (NE (wt)/core (wt): 1.01) are shown in FIG. 25.

We claim:
 1. A solid oral dosage form comprising a plurality ofparticles, each particle comprising: a core comprising an active agentsusceptible to abuse; an internal adhesion promoter in an amount ofabout 0.05% (w/w) to about 10% (w/w) based on total weight of the dosageform; and an alcohol resistant material in an amount of about 1% (w/w)to about 50% (w/w) based on total weight of the dosage form; wherein thecores are (i) dispersed in a matrix comprising a controlled releasematerial or (ii) coated with a controlled release material.
 2. The solidoral dosage form of claim 1, wherein the core further comprises adissolution enhancer in an amount of about 1% (w/w) to about 10% (w/w).3. The solid oral dosage form of claim 1, wherein the coating or matrixfurther comprises a pore former in an amount of about 0.5% (w/w) toabout 25% (w/w).
 4. The solid oral dosage form of claim 1, furthercomprising an external adhesion promoter to promote the adhesion of thealcohol resistant material and the controlled release material in anamount of about 0.05% (w/w) to about 10% (w/w).
 5. The solid oral dosageform of claim 1, wherein the controlled release material is a polymer.6. The solid oral dosage form of claim 1, wherein the controlled releasematerial is an acrylic polymer.
 7. The solid oral dosage form of claim1, wherein controlled release material is a neutral acrylic polymer. 8.The solid oral dosage form of claim 1, wherein the internal adhesionpromoter is selected from the group consisting of a cellulosic material,a surfactant, a carbomer and a mixture thereof.
 9. The solid oral dosageform of claim 8, wherein the cellulosic material is hydroxypropylmethylcellulose.
 10. The solid oral dosage form of claim 8, wherein thesurfactant is a non-ionic surfactant.
 11. The solid oral dosage form ofclaim 10, wherein the non-ionic surfactant is selected from the groupconsisting of a nonoxynol, a sorbitan ester and a mixture thereof. 12.The solid oral dosage form of claim 8, wherein the internal adhesionpromoter is a carbomer.
 13. The solid oral dosage form of claim 2,wherein the dissolution enhancer is a cellulosic material, a sugar, astarch or a polymer.
 14. The solid oral dosage form of claim 2, whereinthe dissolution enhancer is an alkylycellulose.
 15. The solid oraldosage form of claim 2, wherein the dissolution enhancer ismethylcellulose.
 16. The solid oral dosage form of claim 3, wherein thepore former is a polysaccharide, a polymer, an organic solvent or aninorganic material.
 17. The solid oral dosage form of claim 3, whereinthe pore former is selected from the group consisting of sodiumchloride, lactose, dextrose, mannitol, microcrystalline cellulose,methylcellulose and a mixture thereof.
 18. The solid oral dosage form ofclaim 1, wherein the alcohol resistant material is a cellulosicmaterial.
 19. The solid oral dosage form of claim 1, wherein the alcoholresistant material is an alkylcellulose.